The anticancer drug, BCNU, causes potentially life-threatening lung injury in a high percentage of patients. Because changes in the activities of pulmonary and serum angiotensin converting enzyme (ACE) have been previously reported to reflect toxic pulmonary damage by certain agents, we have investigated the effects of BCNU on pulmonary and serum ACE in F344 rats. In vitro, BCNU had a direct inhibitory effect on both serum and pulmonary ACE. This inhibition in vitro was dependent both on time and the concentration of BCNU. In vivo, a large single dose (80 mg/kg, i.p.) did not alter pulmonary ACE nor cause histologically observable acute lung damage. However, serum ACE dropped by 25% within 1 hour after BCNU. A multidose regimen, consisting of 5 mg BCNU/kg once per week for 6 weeks, caused marked pulmonary injury, which continued to develop in severity over several weeks following the completion of dosing. Lung ACE after 4 doses (total of 20 mg BCNU/kg) was depressed by 40% and remained low until dosing was completed. Following the final dose, lung ACE returned to control within 2 weeks. However, after an additional 2 weeks, both lung and serum ACE had decreased by 35% and 25%, respectively, and remained low for the duration of the study. It appears that ACE may provide a useful biochemical monitor for BCNU-induced pulmonary toxicity, but careful attention must be given to the time course of changes in the enzyme activity. ACE as a marker for pulmonary injury can be used not only to monitor the development of lung damage but also can be used to screen potential protectors against the lung damage caused by BCNU administration.